Intracranial Mitochondrial Microparticles Promote Cerebral Edema via Endothelial Injury in Stroke

Vascular endothelial injury underlies the development of severe complications following acute ischemic stroke. While mitochondrial microparticles (mtMPs) compromise endothelial integrity, their mechanistic role in endothelial dysfunction and clinical association with malignant cerebral edema (MCE) remain unclear. We analyzed paired intracranial and peripheral arterial blood samples from patients with anterior circulation large vessel occlusion stroke (LVO-AIS) who underwent thrombectomy. Human brain microvascular endothelial cells were stimulated with intracranial versus peripheral mtMPs, followed by RNA sequencing and analysis. The associations between mtMP levels and MCE were evaluated via multivariate logistic regression and receiver operating characteristic (ROC) analyses. Subgroup and sensitivity analyses were conducted to verify the consistency of the findings. Paired samples (n = 16) revealed higher mtMP levels in intracranial blood than in peripheral blood (P = 0.02). RNA sequencing revealed that intracranial mtMPs altered endothelial gene expression (80 upregulated, 52 downregulated), enriching pattern recognition and proinflammatory pathways, alongside enrichment trends in oxidative stress and neutrophil chemotaxis. In the clinical cohort (n = 90, 20% MCE incidence), intracranial mtMPs were elevated in the MCE group (6.9 ± 1.0 vs. 6.1 ± 1.0, P < 0.01) and were identified as an independent risk factor for MCE (adjusted OR, 2.11 [95% CI, 1.11-4.58], P = 0.04). A composite model integrating intracranial mtMPs with key clinical variables demonstrated an AUC of 0.88 (95% CI 0.81-0.96, P < 0.001). Intracranial mtMPs may contribute to endothelial injury and cerebral edema, offering a potential local biomarker for predicting malignant cerebral edema in patients with LVO-AIS. Trial registrationClinicalTrials.gov, NCT04637074. Registered on November 15, 2020.